Malaria is a disease caused by asexual reproduction of Plasmodium species in the blood. Development of effective vaccines that reduce the severe morbidity and mortality of malaria will require induction of a sustained broadly inhibitory immune response against multiple target antigens. Malaria merozoites are good targets for antibody-based vaccines because the molecules that mediate merozoite invasion into erythrocytes are directly accessible to serum antibodies. Antibodies that can inhibit the function of molecules required for invasion will help eliminate the blood- stage parasites and prevent clinical malaria. In particular, protective immunity directed against the conserved functional domains of merozoite invasion-related molecules will provide effective vaccine targets. Since P. falciparum can use alternate routes of invasion, a multivalent approach is needed to target molecules in each of the potential invasion pathways. MAEBL is a newly identified, highly conserved family of erythrocyte binding proteins expressed in rhoptries and on the surface of malaria merozoites. The chimeric structure of MAEBL suggests that this molecule is involved in an alternate pathway of invasion. The specific aims of this proposal seek to define the importance of MAEBL in the invasion process of Plasmodium falciparum merozoites into human erythrocytes. The long- term goal of this research is to understand how a malaria merozoite invades an erythrocyte in order to facilitate development of vaccines against P. falciparum malaria.